Abstract: Respiratory syncytial virus (RSV) is the most frequent cause of hospitalization for infants and young children, but no vaccines or antiviral drugs are yet available. RSV infects the cells that line the nose, trachea and smaller airways. The overall goal of the laboratory is to understand how RSV infects its target cell, the ciliated airway cell, and to use that information to develop better vaccine and antiviral drug candidates. This laboratory uses primary well differentiated human airway epithelial cultures (HAECs) to study RSV infection. These HAECs have recently been used to identify an important RSV receptor on the ciliated airway cells. Preliminary data presented here demonstrate that the RSV produced by these HAECs is much more infectious for HAECs than for immortalized cells and its attachment, G, glycoprotein is responsible for this difference. The G protein is modified differently in HAECs as it passes through the cell, on its way to being incorporated into the RSV virion at the plasma membrane and this modification may be responsible for its enhanced activity. This project will identify the modification and the mechanism by which it is made. RSV also produces a secreted form of the G protein that triggers immune cells to migrate toward RSV-infected cells. This project will also determine if this secreted G protein is modified like the full-length version, and if its signaling activity is changed or enhanced by its modification, similar to the full-length G protein. Once the modification of the G protein and the secreted G protein are identified, and the mechanism by which they are modified are identified, this information could enable the production of more effective and economical live attenuated vaccines for RSV and provide targets for novel antiviral agents. This project will advance the NIH Mission of developing ?fundamental knowledge to extend healthy life and reduce the burdens of illness.?